Chewable tablet containing phenylephrine

ABSTRACT

A chewable pharmaceutical composition comprising phenylephrine, artificial sweetener, and a substantially aldehyde-free matrix is provided. The composition has phenylephrine stability suitable for a typical commercial product with a two year shelf life. A method of manufacture of the composition and a method of use are also provided.

FIELD OF THE INVENTION

A chewable pharmaceutical composition comprising phenylephrine isprovided. The composition is particularly well suited for the relief ofcold, cough, flu, fever, headache, pain, body ache, migraine, andallergy symptoms.

BACKGROUND OF THE INVENTION

Many commercially available over-the-counter oral cold, cough, flu,fever, and/or allergy preparations contain pseudoephedrine as an activeagent. Although such preparations have been useful, misuse of suchproducts as a starting material for synthesis of illicit substances haslead to the desire to find alternatives that are not suitable for suchillicit synthesis. Phenylephrine is a potential alternative active.However, phenylephrine is susceptible to degradation. The degradation istypically facilitated in excipient compositions of the type typicallyused with pseudoephedrine.

Orally administered pharmaceutical compositions are provided to patientsin many dosage forms, including solid forms such as capsules, caplets ortablets and liquid forms such as solutions, suspensions and liquid fillfor capsules. For many patients including young children, older personsand incapacitated persons, a chewable dosage form is preferable becauseof the ease with which it may be ingested.

Accordingly, it would be desirable to have a palatable, chewable dosageform comprising phenylephrine with reduced propensity for degradation ofphenylephrine.

SUMMARY OF THE INVENTION

The pharmaceutical composition described herein is a chewable oralpharmaceutical composition comprising phenylephrine, an artificialsweetener, and a substantially aldehyde free matrix. The composition hasless than 2.5 wt/wt % total isoquinolines and maintains said level ofisoquinolines for at least 24 months.

The composition may further comprise one or more second active agentsselected from analgesics, decongestants, expectorants, anti-tussives,antipyretics, anti-inflammatory agents, cough suppressants andantihistamines.

In one embodiment mannitol may be used as a diluent.

The composition may be formed in the absence of liquid water at ambienttemperatures.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides an oral chewable pharmaceutical compositioncomprising the pharmaceutical active phenylephrine. The composition ispalatable and has improved phenylephrine stability. The inventorsbelieve with out wishing to be bound to the theory that the selection ofsubstantially aldehyde-free excipients and avoidance of liquid waterand/or heat in the manufacturing process enhance phenylephrinestability. The composition comprises phenylephrine, an artificialsweetener, and a substantially aldehyde free matrix. Roller compactionis exemplary of a suitable method of tableting the composition thatavoids use of liquid water with the composition in the manufacturingprocess and may be accomplished without adding heat (e.g. at ambienttemperature).

Prior to the invention, solid compositions comprising phenylephrine HClwere found to be susceptible to the formation of significant levels ofisoquinoline degradants (often observed in amounts >4%). Phenylephrinecontaining solid compositions are typically more susceptible to theformation of isoquinoline degradants than phenylephrine HCl containingliquid oral dosage forms. The solid phenylephrine comprising compositiondescribed herein comprises less than 2.5% wt/wt total isoquinolines andmaintains said isoquinolines level for at least 24 months. Morepreferably the composition comprises less than 1.5% wt/wt totalisoquinolines and maintains said isoquinoline level for at least 24months.

Phenylephrine HCl has several degradation pathways that formisoquinolines. The inventors believe without wishing to be bound to thetheory that a primary pathway for the formation of isoquinlolinedegradants in prior phenylephrine HCl compositions is the interaction ofPhenylephrine HCl with aldehydes present from flavors and otherexcitipients used in the prior compositions. The aldehydes may be anadded component as in the case of some flavors, for example, or may bethe result of impurities in or degradation products of one or moreexcipients. Moisture, and in some cases the presence of a reducingsugar, also appear to facilitate the formation of isoquinolinesAdditionally, heat may facilitate degradation by oxidative pathways.

Accordingly, the inventors have discovered that degradation ofphenylephrine including degradation to isoquinoline in solidphenylephrine composition may be reduced by use of substantiallyaldehyde-free excipients including substantially aldehyde-free flavorsand minimizing the degradation of excipients. The avoidance of liquidwater and heat in the manufacturing process facilitates minimizingdegradation products. The use of roller compaction as the granulationprocess is exemplary of a suitable manufacturing process.

Roller compaction is a dry granulation process involving the compressionof a blended powder between rollers to produce a solid mass of material.After granulation, this material is milled to a uniform particledistribution with an even distribution of active ingredients. The lackof introduction of water and excess heat to the blend during granulationminimizes any degradation from moisture and heat while providing aconsistent granulation mixture.

In an exemplary embodiment, the oral chewable composition of theinvention comprises phenylephrine HCl as the active ingredient,microcrystalline cellulose, a non-sugar based sweetening system andsubstantially aldehyde-free diluent. The tablet granulation ismanufactured using a roller compaction process to minimize any processrelated degradation.

The composition may contain one or more additional pharmaceuticalactives (also referred to as “active(s)”, “active agent(s)”,“therapeutic agent(s)”, “drug(s)”). Herein reference to “firstpharmaceutical active” means phenylephrine and reference to “secondpharmaceutical active” means any active other than phenylephrine.Further, the term second pharmaceutical active may refer to a singlespecies of active or a plurality of species of actives other thanphenylephrine (e.g., the total number of actives in the compositions maybe greater than 2.)

“Substantially aldehyde-free” means no components with known aldehydefunctionality or components which have aldehyde impurity levels greaterthan 1% or components which are know to readily degrade to aldehydes inthe presence of the tablet matrix disclosed herein are included in thecomposition. The impurity level may be achieved by section of highlypure ingredients and/or removal of aldehydes.

“Matrix” means all components of the composition other than the activeagent(s) and the artificial sweetener including, but not limited to,flavorants, colorants, fillers, binders, disintegrants, preservatives,buffers, natural sweeteners, lubricants, milling agents, glidants,anti-adherents, dispersants, thickeners, solubilizing agents anddiluents.

A “chewable tablet” means a tablet that is formulated to be masticableby a mammal. Such tablets typically have a hardness of about 3-20 KPa,but hardness may vary depending on size and shape of the tablet and thepropensity of the components to solubilize in saliva. Such dosage formsmay be administered without water and are particularly useful foradministration to pediatric patients.

Unless specified otherwise amounts are provided in milligrams per dosageunit which is abbreviated as mg/du. Percentages unless otherwiseindicated are in weight percent.

Preferably the phenylephrine is in a salt form. Suitable salt formsinclude, but are not limited to, phenylephrine hydrochloride (HCl),hydrobromide (H Br), bitartarate and tannate salts. Phenylephrine may beused in an amount of about 0.5 to about 30.0 mg/dosage unit. Preferably,phenylephrine is used in an amount of about 2.5 to about 5.0 mg/dosageunit.

An artificial sweetener is provided to improve palatability. Anartificial sweetener is preferred for use as a sweetener to the use ofconventional sugar sweeteners as the inventors believe, without wishingto be held to the theory, that conventional reducing sugars maycontribute to the degradation of phenylephrine. Suitable artificialsweeteners, include but are not limited to sucralose, saccharine salts,cyclamates, acesulfame K, dipeptide based sweeteners, aspartame andmixtures thereof. Sucralose, which is a high intensity sweetener, isparticularly well suited for use in the composition. Sucralose may beused in an amount of about 1% wt/wt to about 10% wt/wt, for example. Theappropriate amount of artificial sweetener depends on properties andsweetness intensity of the artificial sweetener and target organolepticproperties of the composition. One skilled in the art is familiar withthe characteristics of sweeteners and methods for determining amount ofsweetener to be used.

Suitable additional or second active agents include analgesics,decongestants, expectorants, anti-tussives, antipyretics,anti-inflammatory agents, cough suppressants and antihistamines.

Antihistamines useful in the practice of the present invention (alongwith their preferred salt form) include, but are not limited to,chlorpheniramine (maleate), brompheniramine (maleate);dexchlorpheniramine (maleate), dexbrompheniramine (maleate),triprolidine (HCl), diphenhydramine (HCl, citrate), doxylamine(succinate), tripelenamine (HCl), cyproheptatine (HCl), chlorcyclizine(HCl), bromodiphenhydramine (HCl), phenindamine (tartrate), pyrilamine(maleate, tannate), azatadine (maleate); acrivastine, astemizole,azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine(maleate), desloratadine, loratadine, pheniramine maleate, thonzylamine(HCl), mizolastine and terfenadine.

Antitussives useful in the practice of the present invention (along withtheir preferred salt form) include, but are not limited to,chlophendianol, caramiphen (ediylate), dextromethorphan (HBr),diphenhydramine (citrate, HCl), codeine (phosphate, sulfate) andhydrocodone.

Decongestants useful in the practice of the invention (along with theirpreferred salt form) include, but are not limited to, pseudoephedrine(HCl, sulfate), Ephedrine (HCl, Sulfate), phenylephrine (bitartarate,tannate, HBr, HCl), and phenylpropenolamine (HCl).

Expectorants which may be used in the practice of the invention (alongwith their preferred salt form) include but are not limited to terpinhydrate, guaifenesin (glycerol, guaiacolate), potassium (iodide,citrate) and potassium guaicolsulfonate.

Non-steroidal anti-inflammatory drugs (NSAIDS) which may be used in thepractice of the invention include, but are not limited to, propionicacid derivatives such as ibuprofen, naproxen, ketoprofen, flurbiprofen,fenoprofen, suprofen, fluprofen and fenbufen; acetic acid derivativessuch as tolmetin sodium, zomepirac, sulindac, and indomethacin; fenamicacid derivatives such as mefenamic acid and meclofenamate sodium;biphenyl carboxylic acid derivatives such as diflunisal and flufenisaland oxicams such as piroxicam, sudoxicam and isoxicam.

Cox 2 inhibitors which may be used in the practice of the inventioninclude, but are not limited to, Celecoxib, Rofecoxib and Valdecoxib.

Analgesics which may be used in the practice of the invention includebut are not limited to aspirin, acetominophen, phenacetin and salicylatesalts.

Amounts of pharmaceutically active compounds incorporated areconventional dosages known to those skilled in the art. Further, forpharmaceutical compositions intended for use in the United States,amounts of pharmaceutical actives are preferably in compliance withapplicable FDA regulations regarding dosage of such compounds.

Of the pharmaceutically active compounds described above which may beincluded in addition to phenylephrine in the composition, those whichare particularly preferred are set forth below along with preferredranges for their inclusion into the claimed pharmaceutical composition.

Chlorpheniramine may be used in the pharmaceutical composition inamounts between about 1 mg/du and about 8 mg/du. Preferablychlorpheniramine, when used in the pharmaceutical composition, ispresent in the amount of about 1 mg/du to about 4 mg/du.

Brompheniramine maleate may be used in the pharmaceutical composition,preferably in the amount of about 1 mg/du to about 4 mg/du.

Dextromethorphan HBr may be used in the pharmaceutical composition, inthe amount of about 15 mg/du to about 30 mg/du.

Guaifenesin may be used in the composition in amounts of about 25 mg/duto about 200 mg/du and preferably in amounts of about 25 mg/du to about100 mg/du.

Acetaminophen may be used in the composition in amounts of about 60mg/du to about 1000 mg/du and preferably in amounts of about 60 mg/duabout 325 mg/du.

Chlophedianol may be used in the composition in amounts of about 10mg/du to about 25 mg/du.

Diphenhydramine may be used in the composition in amounts of about 5mg/du to about 50 mg/du and preferably in amounts of about 5 mg/du toabout 25 mg/du.

Loratadine may be used in the composition in amounts of about 2.5 mg/duto about 10 mg/du and preferably in amounts of about 2.5 mg/du to about5.0 mg/du.

Aspirin may be used in the composition in amounts of about 160 mg/du toabout 650 mg/du and preferably in amounts of about 160 mg/du to about320 mg/du.

Doxylamine may be used in the composition in amounts of about 3.7 mg/duto about 25 mg/du and preferably in amounts about 3.75 mg/du to about12.5 mg/du.

The pharmaceutically active compounds are preferably of a compendialgrade such as, for example, of N.F. (National Formulary) or U.S.P.(United States Pharmacopeia) grade.

Excipients known by those skilled in the art may be useful in thepractice of the present invention. Such excipients may include, but arenot limited to, flavorants, colorants, fillers, binders, disintegrants,preservatives, pH adjustment agents, natural sweeteners, lubricants,milling agents, glidants, anti-adherents, dispersants, thickeners,solubilizing agents, diluents, preservatives, antioxidants, and tastemasking agents.

Diluents useful in the practice include polyols such as mannitol.Diluents with aldehyde functionality, aldehyde impurities, or apropensity to form aldehyde degradants are preferably avoided. For thematerials tested, the inventors found tablets made with mannitol, to beless susceptible to degradation than tablets made with sorbitol orxylitol. It is not known if this is due to inherently superiorproperties of mannitol or whether this is due to specific features ofthe lots of material tested.

Anti-oxidants may be included in the composition. Propyl gallate isexemplary of an antioxidant that is suitable for use in the composition.

Dicarboxylic and tricarboxylic organic acids may be used as pHadjustment agents Fumaric acid and citric acid are exemplary of suitablepH adjustment agents. It is preferable to adjust the composition tomaintain the pH less than about 6 when placed in water.

Coloring agents may also be incorporated in the pharmaceuticalcomposition to provide an appealing color to the composition. Thecoloring agents should be selected to avoid chemical incompatibilitieswith other ingredients in the composition. Suitable coloring agents arewell known to those skilled in the art.

A binder may be included in the composition. Exemplary binders include,but are not limited to, polyethylene oxide, hydroxypropylmethylcellulose (i.e., HPMC or hypromellose), and povidone.

Lubricants suitable for use in the composition include, but are notlimited to stearic acid, magnesium stearate, and glyceryl behenate.

Microcrystalline cellulose is exemplary of a filler suitable for use inthe practice of the invention. Microcrystalline cellulose iscommercially available from suppliers such as FMC (1735 Market Street,Philadelphia, Pa. 19103) under the trade name Avicel™

Typically, addition of a flavorant is desirable in a chewable tablet toenhance palatability. The flavorant should be substantially free ofaldehyde functionality. Accordingly, it is desirable that to both avoidflavors with aldehyde functionality and flavors provided in a mediumthat contains aldehydes. Addition of a flavorant is desirable in achewable tablet. Examples of suitable flavorants include, but are notlimited to, natural and artificial flavors such as mints (i.e.,peppermint, etc.), menthol, chocolate, artificial chocolate, bubblegum,both artificial and natural fruit flavors (i.e., cherry, grape, orange,strawberry, etc.), debittering flavors and combinations of two or morethereof. Flavoring agents are generally provided in the composition inamounts effective to provide palatable flavor to the compositions.Typically, flavoring agents are present in amounts in the range of about0 grams to about 5 grams per 100 grams of the composition.

Agents which adjust “mouth feel” (e.g. organoleptic properties) may beincluded in the composition. Glycine and kappa caragenen are exemplaryof agents which adjust “mouth feel”. Glycine may be used in amounts ofabout 2 to about 20 mg/du, for example

Glidants may be included in the composition. Silicon dioxide isexemplary of a suitable glidant.

Optionally, preservatives may be included in the composition.Preservatives useful in the present invention include but are notlimited to sodium benzoate, sorbates, such as potassium sorbate, saltsof edetate (also known as salts of ethylenediaminetetraacetic acid orEDTA, such as disodium edetate), benzaldionium chloride and parabens(such as methyl, ethyl, propyl, and butyl p-hydroxybenzoic acid esters).Preservatives listed above are exemplary, but each preservative must beevaluated on an experimental basis, in each formulation to assurecompatibility and efficacy of the preservative. Methods for evaluatingthe efficacy of preservatives in pharmaceutical formulations are knownto those skilled in the art. Sodium benzoate and disodium edetate arethe presently preferred preservative ingredients.

Excipients should be selected and amounts adjusted such that thecomposition exhibits good flow properties under gravity flow conditions,have cohesive properties and be compressible. For example, addition of abinder and/or adjustment of the amount of binder may be used tofacilitate compressibility.

In an exemplary embodiment, the active agent(s) is pre-blended with adiluent, binder and other excipients in a mixing vessel such as, forexample, a V-Blender. Upon mixing, the resulting blend, may be fed,typically by gravity, to the hopper of a roller compactor.

In a typical roller compaction process, a vertical feed screw (i.e., a“VFS”) facilitates feeding the blend into the compactor by deareatingthe blend and forcing it between the rolls. A horizontal feed screw(i.e., a “HVS”) within the hopper feeds the material to VFS. The feedscrew speeds (rpm) of the VFS and HFS may be adjusted to optimize theamount of blend going into the roll nip region of the roller compactor.In one exemplary embodiment the ratio of VFS:HFS speed is about 3:1.

The blend is densified and granulated, as it passes between twohigh-pressure rolls that compress the blend. Controlling and monitoringroll speed (which impacts dwell time for the material to be compacted bythe rolls), roll pressure (which is the pressure applied to the rolls)and/or roll gap (which is a function of the pressure applied to therolls and the material passing between them) facilitates maintaininguniformity and batch-to-batch reproducibility.

The compacted material is collected and passed thru a mill for particlesizing. Once sized the compacted material may be tableted directly orblended with additional ingredients and tableted.

Roller compaction is exemplary of one method for preparing thecomposition of the invention. Other dry granulation methods such asslugging, for example, may be likewise suitable.

Typically, the composition is provided to a patient in need of treatmentin a dosage unit of 1-2 tablets per dosage units although other dosageunits may be likewise suitable. The dosage unit may be provided as asingle dosage unit or multiples thereof, based on age, weight and otherhealth parameters determined by a physician to be relevant.

EXAMPLE 1

An exemplary composition comprising the single first pharmaceuticalactive phenylephrine is provided in Table 1. This composition isrepresentative and one of many composition that are within the scope ofthe invention. The exemplary embodiment is provided for illustrativepurposes.

TABLE 1 Amount Ingredient (mg/du) Phenylephrine HCl 2.50 Mannitol 175Microcrystalline Cellulose (MCC) 75 Fumaric acid 21 Glycine 15 Color 1Artificial Sweetener 5 Flavorant 10 Magnesium stearate 2.5 Polyethyleneoxide 17

The composition of Table 1 may be prepared by roller compaction asdescribed herein.

EXAMPLE 2

An exemplary composition comprising phenylephrine and a second activeBrompheniramine maleate is provided in Table 2. This composition isrepresentative and one of the many compositions that are within thescope of the invention. The exemplary embodiment is provided forillustrative purposes.

TABLE 2 Amount Ingredient (mg/du) Phenylephrine HCl 2.5 BrompheniramineMaleate 1 Mannitol 175 Microcrystalline Cellulose 75 Fumaric acid 21Glycine 15 Colorant 1 Artificial flavor 10 Magnesium stearate 2.5Polyethylene oxide 17

The composition of Table 2 may be prepared by roller compaction asdescribed herein.

EXAMPLE 3

Table 3 provides degradation data for an exemplary embodiment of thecomposition of the invention comprising substantially aldehyde-freeexcipients and a similar composition comprising an aldehyde containingflavorant.

TABLE 3 Condition (Temperature ° C./% relative Time % Sample humidity)point (week) Degradants Substantially Ambient Initial 0.071 AldehydeFree 40/75 2 .089 composition 40/75 4 .070 40/75 8 .100 40/75 12 0.33940/75 16 0.284 Composition Ambient Initial 0.524 with Aldehyde 40/75 21.705 containing flavorant 40/75 4 2.392 (vanilla) 40/75 8 3.253 40/7512 4.831 40/75 16 4.159

EXAMPLE 4

Table 4 provides degradation data for an exemplary embodiment of thecomposition of the invention comprising substantially aldehyde-freeexcipients prepared by roller compaction and a similar compositionprepared by wt granulation methods.

TABLE 4 Condition (Temperature ° C./% relative Time % Sample humidity)point (week) Degradants Composition Ambient Initial 0.071 prepared byRoller 40/75 2 .089 Compaction 40/75 4 .070 40/75 8 .100 40/75 12 0.33940/75 16 0.284 Composition 40/75 16 1.039 prepared by Wet Granulation

Although the foregoing invention has been described in some detail byway of illustrations and examples for purposes of clarity ofunderstanding, it will be obvious that certain changes and modificationsmay be practiced within the scope of the appended claims. Modificationsof the above-described modes of practicing the invention that areobvious to persons of skill in the art are intended to be includedwithin the scope of the following claims.

1-38. (canceled)
 39. A chewable composition comprising: a). phenylephrine; b). an artificial sweetener; and c). a matrix comprising substantially aldehyde-free excipients and an aldehyde-free flavorant.
 40. The composition of claim 39 wherein the composition further comprises less than 2.5% wt/wt total isoquinolines and maintains said level of isoquinolines for at least 24 months.
 41. The composition of claim 39, wherein the composition further comprises less than 1.5% wt/wt total isoquinolines and maintains said level of isoquinolines for at least 24 months.
 42. The composition of claim 39, further comprising at least one second pharmaceutical active.
 43. The composition of claim 42, wherein the at least one second active agent is selected from the group consisting of analgesics, decongestants, expectorants, antitussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.
 44. The composition of claim 43, wherein the at least one second active agent is selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen, fluprofen, fenbufen, tolmetin sodium, zomepirac, sulindac, indomethacin, mefenamic acid, meclofenamate sodium, diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam, chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine, doxylamine succinate, tripelenamine, cyproheptatine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, astemizole, azelastine, cetirizine, ebastine, fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine, pheniramine, thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen, dextromethorphan, diphenhydramine, codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine, terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate, Celecoxib, Rofecoxib, Valdecoxib, aspirin, acetaminophen, phenacetin, salicylate salts and combinations thereof.
 45. The composition of claim 44, wherein the at least one second active agent is selected from the group consisting of chlorpheniramine, brompheniramine, dextromethorphan, guaifenesin, acetaminophen, chlophendianol, diphenhydramine, loratadine, aspirin, and doxylamine succinate
 46. The composition of claim 39, wherein the artificial sweetener is selected from the group consisting of sucralose, saccharine salts, cyclamates, acesulfame K, aspartame and mixtures thereof.
 47. The composition of claim 46, wherein the artificial sweetener comprises sucralose.
 48. The composition of claim 39, wherein the substantially aldehyde-free flavorant is selected from the group consisting of mints, menthol, chocolate, artificial chocolate, bubblegum, artificial fruit flavors, natural fruit flavors, debittering flavors and combinations thereof.
 49. The composition of claim 39, wherein the matrix comprises an antioxidant.
 50. The composition of claim 49, wherein the antioxidant is propyl gallate.
 51. The composition of claim 39, wherein the matrix comprises mannitol.
 52. A chewable tablet comprising: a). phenylephrine; b). an artificial sweetener; c). a matrix comprising substantially aldehyde-free excipients; and d.) optionally aldehyde-free flavorant.
 53. The chewable tablet of claim 52, wherein the tablet further comprises a.) less than 2.5 % wt/wt total isoquinolines and maintains said level of isoquinolines for at least 24 months; and b.) wherein the tablet is formed in the absence of liquid water at substantially ambient temperature.
 54. The chewable tablet of claim 52, further comprising at least one second pharmaceutical active.
 55. The chewable tablet of claim 54, wherein the at least one second active agent is selected from the group consisting of analgesics, decongestants, expectorants, anti-tussives, antipyretics, anti-inflammatory agents, cough suppressants and antihistamines.
 56. The chewable tablet of claim 55, wherein the at least one second active agent is selected from the group consisting of ibuprofen, naproxen, ketoprofen, flurbiprofen, fenoprofen, suprofen, fluprofen, fehbufen, tolmetin sodium, zomepirac, sulindac, indomethacin, mefenamic acid, meclofenamate. sodium, diflunisal, flufenisal, oxicams, piroxicam, sudoxicam, isoxicam, chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, chlorcyclizine, diphenhydramine, doxylamine, tripelenamine, cyproheptatine, romodiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, astemizole, azelastine, cetirizine, ebastine; fexofenadine, ketotifen, carbinoxamine, desloratadine, loratadine, pheniramine, thonzylamine, mizolastine, terfenadine, chlophendianol, caramiphen, dextromethorphan, diphenhydramine, codeine, hydrocodone, pseudoephedrine, ephedrine, phenylephrine, phenylpropenolamine, terpin hydrate, guaifenesin, potassium, potassium guaicolsulfonate, Celecoxib, Rofecoxib, Valdecoxib, aspirin; acetaminophen, phenacetin, salicylate salts and combinations thereof.
 57. The chewable tablet of claim 56, wherein the at least one second active agent is selected from the group consisting of chlorpheniramine, brompheniramine, dextromethorphan, guaifenesin, acetaminophen, chlophendianol, diphenhydramine, loratadine, aspirin, and doxylamine succinate
 58. The chewable tablet of claim 52, wherein the artificial sweetener is selected from the group consisting of sucralose, saccharine salts, cyclamates, acesulfame K, aspartame and mixtures thereof.
 59. The tablet of claim 52, wherein the matrix comprises an antioxidant.
 60. The tablet of claim 59, wherein the antioxidant is propyl gallate.
 61. The tablet of claim 53, wherein the matrix comprises mannitol.
 62. A method of treating an mammal in need of treatment comprising providing an effective amount of a chewable composition comprising phenylephrine, artificial sweetener, and a matrix comprising substantially aldehyde-free excipients and optionally aldehyde-free flavorant, wherein the composition further comprises less than 2.5% wt/wt total isoquinolines and maintains said level of isoquinolines for at least 24 months. 